Constant light uncovers behavioral effects of a mutation in the schizophrenia risk gene Dtnbp1 in mice

Various psychiatric disorders, including schizophrenia, are comorbid with sleep and circadian rhythm disruptions. To understand the links between circadian rhythms and schizophrenia, we analyzed wheel-running behavior of Sandy (Sdy) mice, which have a loss-of-function mutation in the schizophrenia risk gene Dtnbpl, and exhibit several behavioral features of schizophrenia. While rhythms of Sdy mice were mainly normal under light-dark conditions (LD) or in constant darkness (DD), they had a significantly longer free-running period under constant light (LL) compared to wild-type (WT) littermates. The mutant mice also had a higher subjective day/subjective night ratio of activity under LL, indicating lower amplitude, and a lower precision of their onsets of activity under all three lighting conditions. These observations are reminiscent of the circadian disruptions observed in schizophrenia patients. This prompted us to assess schizophrenia-relevant behavioral abnormalities in Sdy mice following alteration of the circadian rhythms by presentation of constant light. Spontaneous locomotor activity, prepulse inhibition (PPI) of acoustic startle and anxiety-like behavior were assessed under baseline LD conditions, then in LL, and then again in LD. Under LL, the Sdy mice showed significantly increased spontaneous locomotion as well as deficits in PPI compared to WT mice. Strikingly, these behavioral deficits persisted even after the mice were returned in LD conditions. While LL led to an increase in anxiety-like behavior in WT animals that was fully reversed after 3 weeks in LD, this effect was not observed in the Sdy mutants. Overall, these results suggest that Dtnbp1 deficiency may lead to increased vulnerability to schizophrenia under environmental conditions where circadian rhythms are altered. (C) 2015 Elsevier B.V. All rights reserved.